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Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Alzheimer's disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer's Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD.

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Distinct neuronal and glial tau pathologies define corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Additional Alzheimer disease, TDP-43, and Lewy body copathologies are also common. The interplay of these pathologies with clinical symptoms remains unclear as individuals can present with corticobasal syndrome, frontotemporal dementia, PSP, or atypical Parkinsonism and may have additional secondary impairments. We report clinical, pathological, and genetic interactions in a cohort of CBD and PSP cases. Neurofibrillary tangles and plaques were common. Apolipoprotein E (APOE)ε4 carriers had more plaques while PSP APOEε2 carriers had fewer plaques. TDP-43 copathology was present and age-associated in 14% of PSP, and age-independent in 33% of CBD. Lewy body copathology varied from 9% to 15% and was not age-associated. The primary FTD-Tau burden-a sum of the neuronal, astrocytic and oligodendrocytic tau-was not age-, APOE-, or MAPT-related. In PSP, FTD-Tau, independent of copathology, associated with executive, language, motor, and visuospatial impairments, while PSP with Parkinsonism had a lower FTD-Tau burden, but this was not the case in CBD. Taken together, our results indicate that the primary tauopathy burden is the strongest correlate of clinical PSP, while copathologies are principally determined by age and genetic risk factors.

The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

ObjectiveParkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression.MethodsWe screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database.ResultsGenotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005).InterpretationOur study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

BACKGROUND. From March 2, 2020, to April 12, 2020, New York City (NYC) experienced exponential growth of the COVID-19 pandemic due to novel coronavirus (SARS-CoV-2). Little is known regarding how physicians have been affected. We aimed to characterize the COVID-19 impact on NYC resident physicians. METHODS. IRB-exempt and expedited cross-sectional analysis through survey to NYC residency program directors April 3-12, 2020, encompassing events from March 2, 2020, to April 12, 2020. RESULTS. From an estimated 340 residency programs around NYC, recruitment yielded 91 responses, representing 24 specialties and 2306 residents. In 45.1% of programs, at least 1 resident with confirmed COVID-19 was reported. One hundred one resident physicians were confirmed COVID-19-positive, with an additional 163 residents presumed positive for COVID-19 based on symptoms but awaiting or unable to obtain testing. Two COVID-19-positive residents were hospitalized, with 1 in intensive care. Among specialties with more than 100 residents represented, negative binomial regression indicated that infection risk differed by specialty (P = 0.039). In 80% of programs, quarantining a resident was reported. Ninety of 91 programs reported reuse or extended mask use, and 43 programs reported that personal protective equipment (PPE) was suboptimal. Sixty-five programs (74.7%) redeployed residents elsewhere to support COVID-19 efforts. CONCLUSION. Many resident physicians around NYC have been affected by COVID-19 through direct infection, quarantine, or redeployment. Lack of access to testing and concern regarding suboptimal PPE are common among residency programs. Infection risk may differ by specialty. FUNDING. National Eye Institute Core Grant P30EY019007; Research to Prevent Blindness Unrestricted Grant; Parker Family Chair; University of Pennsylvania., Introduction The United States is part of a global pandemic known as COVID-19 (1), which has characteristics that overlap with the Spanish flu of 1918. The causative novel coronavirus (2019-nCoV, [...]

Purpose: Early cognitive symptoms such as word-finding difficulty (WFD) in daily conversation are common in Parkinson's disease (PD), but studies have been limited by a lack of feasible, quantitative measures. Linguistic analysis, focused on pauses in speech, may yield markers of impairment of cognition and communication in PD. The objective of this study was to evaluate the relationship of linguistic markers in semistructured speech to WFD symptoms and cognitive function in PD. Method: Speech recordings of description of the Cookie Theft picture in 53 patients with PD without dementia and 23 elderly controls were analyzed with Praat software. Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005), category naming fluency, and confrontation naming tests were administered. Questionnaires rating WFD symptoms and cognitive instrumental activities of daily living were completed. We determined the relationships between (a) pause length and location, (b) MoCA score, and (c) WFD symptoms, using Pearson's correlations and multivariate regression models. Results: Compared with controls, patients with PD had more pauses within utterances as well as fewer words per minute and a lower percentage of well-formed sentences. Pauses within utterances differed significantly between PD--mild cognitive impairment and normal cognition (p < 0.001). Words per minute and percentage of well-formed sentences were predictive of MoCA in multivariate regression models. Pauses before verbs were associated with patient-reported severity of WFD symptoms (p = .006). Conclusions: Linguistic markers including pauses within utterances distinguish patients with PD with mild cognitive symptoms from elderly controls. These markers are associated with global cognitive function before the onset of dementia. Pauses before verbs and grammatical markers may index early cognitive symptoms such as WFD that may interfere with functional communication.

Apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for Alzheimer's disease (AD) and it is thought to do so by modulating levels of its product, apolipoprotein E (Apo-E), and regulating amyloid-β (Aβ) clearance. However, information on clinical and biomarker correlates of Apo-E proteins is scarce. We examined the relationship of cerebrospinal fluid (CSF) and plasma Apo-E protein levels, and APOE genotype to cognition and AD biomarker changes in 311 AD neuroimaging initiative subjects with CSF Apo-E measurements and 565 subjects with plasma Apo-E measurements. At baseline, higher CSF Apo-E levels were associated with higher total and phosphorylated CSF tau levels. CSF Apo-E levels were associated with longitudinal cognitive decline, MCI conversion to dementia, and gray matter atrophy rate in total tau/Aβ1-42 ratio and APOE genotype-adjusted analyses. In analyses stratified by APOE genotype, our results were only significant in the group without the ε4 allele. Baseline CSF Apo-E levels did not predict longitudinal CSF Aβ or tau changes. Plasma Apo-E levels show a mild correlation with CSF Apo-E levels, but were not associated with longitudinal cognitive and MRI changes. Based on our analyses, we speculate that increased CSF Apo-E2 or -E3 levels might represent a protective response to injury in AD and may have neuroprotective effects by decreasing neuronal damage independent of tau and amyloid deposition in addition to its effects on amyloid clearance.

Background: Missing data is prevalent in the Alzheimer's Disease Neuroimaging Initiative (ADNI). It is common to deal with missingness by removing subjects with missing entries prior to statistical analysis; however, this can lead to significant efficiency loss and sometimes bias. It has yet to be demonstrated that the imputation approach to handling this issue can be valuable in some longitudinal regression settings. Objective: The purpose of this study is to demonstrate the importance of imputation and how imputation is correctly done in ADNI by analyzing longitudinal Alzheimer's Disease Assessment Scale –Cognitive Subscale 13 (ADAS-Cog 13) scores and their association with baseline patient characteristics. Methods: We studied 1,063 subjects in ADNI with mild cognitive impairment. Longitudinal ADAS-Cog 13 scores were modeled with a linear mixed-effects model with baseline clinical and demographic characteristics as predictors. The model estimates obtained without imputation were compared with those obtained after imputation with Multiple Imputation by Chained Equations (MICE). We justify application of MICE by investigating the missing data mechanism and model assumptions. We also assess robustness of the results to the choice of imputation method. Results: The fixed-effects estimates of the linear mixed-effects model after imputation with MICE yield valid, tighter confidence intervals, thus improving the efficiency of the analysis when compared to the analysis done without imputation. Conclusions: Our study demonstrates the importance of accounting for missing data in ADNI. When deciding to perform imputation, care should be taken in choosing the approach, as an invalid one can compromise the statistical analyses. [ABSTRACT FROM AUTHOR]

This study aims to design and pilot an empirically based mobile application (ActiviDaily) to increase daily activity in persons with apathy and ADRD and test its feasibility and preliminary efficacy. ActiviDaily was developed to address impairments in goal-directed behaviour, including difficulty with initiation, planning, and motivation that contribute to apathy. Participants included patients with apathy and MCI, mild bvFTD, or mild AD and their caregivers. In Phase I, 6 patient-caregiver dyads participated in 1-week pilot testing and focus groups. In Phase II, 24 dyads completed 4 weeks of at-home ActiviDaily use. Baseline and follow-up visits included assessments of app usability, goal attainment, global cognition and functioning, apathy, and psychological symptoms. App use did not differ across diagnostic groups and was not associated with age, sex, education, global functioning or neuropsychiatric symptoms. Patients and care-partners reported high levels of satisfaction and usability, and care-partner usability rating predicted app use. At follow-up, participants showed significant improvement in goal achievement for all goal types combined. Participant goal-directed behaviour increased after 4 weeks of ActiviDaily use. Patients and caregivers reported good usability and user satisfaction. Our findings support the feasibility and efficacy of mobile-health applications to increase goal-directed behaviour in ADRD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Variability in relationship of tau‐based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non‐specific nature of N, modulated by non‐AD co‐pathologies, age‐related changes, and resilience factors. METHODS: We used regional T‐N residual patterns to partition 184 patients within the Alzheimer's continuum into data‐driven groups. These were compared with groups from 159 non‐AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T‐N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T‐N mismatch patterns resembling neurodegeneration patterns in non‐AD groups, similarly associated with non‐AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T‐N mismatch correlated with TDP‐43 co‐pathology. DISCUSSION: T‐N mismatch may provide a personalized approach for determining non‐AD factors associated with resilience/vulnerability in AD. [ABSTRACT FROM AUTHOR]

An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among 10 neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in 16 brain regions from 671 cases with diverse neurodegenerative diseases are summarized and analyzed. These include: 1) amyloid-β and tau lesions in Alzheimer's disease; 2) tau lesions in three other tauopathies including Pick's disease, progressive supranuclear palsy and corticobasal degeneration; 3) α-synuclein inclusion ratings in four synucleinopathies including Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy; and 4) TDP-43 lesions in two TDP-43 proteinopathies, including frontotemporal lobar degeneration associated with TDP-43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category.